Current Drug Metabolism

Although the invention of a new drug molecule is a very rigorous, specialized, time-consuming and costly process, it is vital for identifying the solutions to modern age-associated, complex and lifestyle-related diseases. The primary hurdle in the invention of a new drug molecule is to predict and analyze its effects on the metabolism of the drug itself and its effect on the metabolism of the person. The interaction of drug molecules with different tissues and organs is highly dynamic, multifold, influenced by several factors and most of the time, it is unpredictable. Hence, the application of drugs for the treatment of the disease may be associated with several undesirable effects. It is therefore essential to understand the factors that influence the dynamics of the drug in the biological system. Both pharmacodynamics and pharmacokinetics are important in understanding the interactions of the drug with living organisms and are essential in determining the drug dose, benefits, and adverse effects. Furthermore, the determination of toxicity is of utmost importance, given the fact that several blockbuster drugs are being withdrawn from the market. Several factors regulate the dynamicity of the drug molecule in the living organism and it is not limited to environment, drug delivery methods, the gender of the individual, the form of the drug, route and time of drug administration. This special issue has reviewed certain factors that can influence the efficacy of the drug in the living organism and have envisaged the way to curtail their effects in order to make the drug safe to the patient [1-6]. Several environmental factors such as radiation and pollutants can influence the activity of several drug-metabolizing enzymes and hence the metabolism of drugs [1]. Furthermore, the individual-specific factors such as genetic polymorphisms, physiological condition, pathological conditions and life-style related factors such as smoking, alcohol consumption, nutrition, etc. can modulate the metabolism of a drug in a person’s body. Sex and gender of a person are involved in the metabolism of drug molecules and they are usually the most neglected factors in predicting and analyzing the effect of a drug. The influence of sex and gender is essential in understanding and avoiding sex-related adverse effects of drugs. Specific emphasis is required to understand the involvement of genomic and non-genomic action of sex hormones [2]. Phytochemicals have been used for a long time for the treatment of various diseases, however, poor bioavailability is a major concern. Poor bioavailability may be due to the metabolism of phytochemicals that are mostly dependent on the form of phytochemicals and individual- specific variations. Therefore, understanding the metabolism and pharmacokinetics of phytochemicals might extend their therapeutic use [3]. Poor bioavailability and severe side effects are the major limitations in the therapeutic use of many types of drugs. This can be efficiently overcome by employing nanocarrier or nanoparticle-based drug delivery systems and it can not only improve the quality of life and lead to a reduction in the overall cost of treatment [4, 5]. Due to increasing interest in the nanoparticles-based delivery of drugs, it has become more efficient and less toxic. However, still, efforts are required to understand the differential metabolism of the nanoform of a drug versus a native drug that may further reduce their side effects and enhance safety. Amongst many diseases related to modern lifestyle, age and environmental effect, cancer is posing increasing pressure on the medicine and health care systems for the invention of new therapeutic ways. Drug resistance in cancer is the probable reason behind the increasing risk of cancer and may warrant parallel attention as that of antibiotic-resistant bacteria. Drug resistance in cancer may be due to an altered gene expression, modulated gene expression regulation and altered DNA repair mechanisms of the major drug transporter proteins. Cancer cells achieve this by epigenetic mechanisms, particularly, the methylation of the promoter region of the drug transporter proteins, expression of specific microRNAs, etc. [6]. Therefore, understanding these mechanisms may suggest us future directions for better treatment. Cancer cachexia is a major complication of advanced cancers and is associated with many complications, particularly, the skeletal muscle wasting. Mitochondria play a very important role in the development of cancer cachexia, particularly, in the regulation of total protein turnover in skeletal muscles [7]. Hence, mitochondria are a very important target in the prevention and treatment of cancer cachexia.

Cancer refers to the uncontrolled growth of abnormal cells in the body [1]. As estimated by from the American Cancer Society, there are about 1,762,450 new cancer cases and 606,880 cancer deaths cases in 2019 [2]. With the numerous advances in cancer therapy research, the survival rate has improved by five percent. Due to chemoresistance developed by the tumor cells, there is no definite cure for many cancers; multidrug resistance allows for metastasis and disease recurrence [3]. Phytochemical extracts are highly effective against cancers and various degenerative diseases [4, 5]. They possess potentiating features including antioxidant, anti-inflammatory, and anti-tumor properties [6]. Regular intake of phytochemicals has shown to improve an individual’s health status [4, 6]. Additionally, phytochemical combinational therapy is less toxic to healthy cells, produces fewer symptoms, and preferentially sensitizes tumor cells to chemo drugs. Non-coding RNAs makeup an emerging strategy expected to decrease chemoresistance by altering the regulation of various tumor suppressor genes and oncogenes against. Thus, these ncRNA can be used as biomarkers or therapeutic target for cancers [7]. Although the advanced therapeutic strategies are yet to be developed, including natural products a patient’s daily diet may help decrease cancer incidence. In continuation of volume 20 issue 12, we would like to potentiate our volume with more serious malignant diseases and the chemoresistance developed by the cancer cells. This volume focuses mostly on neuroblastoma, lung cancer, and cervical cancer correlated with their biology, therapy, and resistance development. Neuroblastoma is a common pediatric disease diagnosed in children of ages 1 to 5. This cancer, generally arises in adrenal glands or within a bundle of neural cells often in the chest, neck, or spine. Secondly, lung cancer is the second most common cancer detected in men and women. As per the estimation of the American Cancer Society, for the year 2020, about 228,820 new cases and 135,720 deaths are expected. Cervical cancer is another serious cancer; it is the fourth most frequently diagnosed disease in females, with as an estimated percentile of about 6.6% for the year 2018. Metabolic fluctuations, including insulin resistance, triglyceride levels, obesity, and irregularity of adiponectin cause cervical cancer. Adiponectin is a hormone secreted from adipose tissue and found in blood plasma. Moreover, the concentration of adiponectin is inversely associated with the an increased risk of cancers like cervical cancer. This volume focuses on adiponectin and its role in cervical cancer. Previous research has shown that adiponectin downregulates the expression of cyclin D1 and c-myc while upregulating p53, allowing for apoptosis cell proliferation the inhibition. Thus, adiponectin expression can be taken as a biomarker for cervical cancer diagnosis. In addition to the cancers, we focus on Alzheimer disease as well. This disease is an irreversible and progressive age-related neurodegenerative disease detected worldwide. There are no current reliable therapies for this disease; acetylcholinesterases are somewhat effective for neuropsychiatric symptoms. However, the new therapeutically plant derived agents have demonstrated improved results. Various studies on phytochemicals have determined that their use of these may reduce the onset and progression of the disease, including age and insulin related neuropathology in Alzheimer’s disease. Chemoresistance remains a major obstacle in the therapy of cancer and presents a challenge for improvising the clinical research for a better outcome. Phytochemicals are naturally occurring plant-based compounds that exhibit anti-cancer properties and reduce chemoresistance development, thereby reducing relapse and metastasis. Chemoresistance mostly occurs due to aberrantly acting transporter pump proteins, mitochondrial alterations, EMT, oncogenes, DNA repair proteins, and cancer stemness. Our volume includes the biology of the molecular mechanisms behind as to determine which genes function abnormally and which can be targeted for therapy. Understanding how the cells develop resistance is essential for enhancing therapy and sensitizing the cells to the chemodrug. As phytochemicals are natural extracts that interfere with the self-renewal, drug resistance, they may be useful in combinational therapies. Our volume will describe phytochemicals and their mechanisms in the drug resistance pathway. This is a potential milestone in the cancer therapy as, the synthetic drugs currently are toxic to healthy cells and weaken a patient’s immune system. Additionally, our volume includes topics about the noncoding RNAs (ncRNAs). These ncRNAs are large segments of the human transcriptome that play a crucial role in cellular physiology and pathogenesis. At present, they are widely explored and encouraged for the cancer therapy, ncRNAs help regulate transcription; they work as transcriptional activators, RNA polymerase, and duplex DNA to regulate genes that develop drug resistance pathways. Thus, targeting ncRNA could be an effective novel therapeutic strategy for various cancers like lung cancer. The discussed topics herein would summarize the research done previously and would describe how phytochemicals may be used to overcome chemoresistance in cancer therapy as well as degenerative diseases. It is our pleasure to present this comprehensive summary of revised therapeutic strategies of cancer to the research community for a clear and holistic understanding. Thus, we hope our work on these volumes reflects novel therapeutic ideas for improved patient care.

One of the major challenges currently facing cancer therapy is the development of drug resistance either intrinsically or as a result of treatment. Treatment evasion is mediated by an intricate web of signalling cascades and adaptations caused by selective therapeutic pressure, leading to metastatic spread and patient death. Hence, discovering and designing novel therapeutic compounds and regimens based on specific alterations in the cancer microenvironment and capable of overcoming resistance to traditional therapies is necessary to improve cancer survival outcomes. These new therapeutic modalities should exhibit improved solubility, penetration capacity and bioavailability in the tumor microenvironment as well as enhanced target specificity compared to old generation compounds. The success of this endeavour will contribute to the advent of precision medicine leading to personalized therapeutic approaches for patients.

Exosomes are cell-derived Nano vesicles, which can mediate intracellular communication by transferring exosome messages such as mRNA, miRNA, protein, and etc. It has been reported that exosomes play important roles in antigen presentation, occurrence and progress of tumors, and signal transduction of neurons. Besides, exosome acts as a carrier for targeted drug delivery, carrying mRNA and miRNA to places where diseases are located and reaching the goal of targeted therapy. Therefore, it can be used as drug delivery vehicle for numerous diseases. However, the hypothesis of using exosomes to deliver therapeutic cargo is still in initial stage considering the heterogeneity and individualized genetic background of the tumor cells. Numerous studies showed that multiple types of cells secrete exosomes, including immunocytes, cardiovascular cells, neurocytes, stem cells, cancer cells and so on, to play biological or pathological effect like antigen presentation, RNA transport, tissue reconstruction, neurodegenerative disorder, tumor metastasis, metabolism and so on. Some signal molecules like specific proteins, lipid or nucleic acids have a biological effect through exosomes transportation. The universality of exosome and convenience of obtaining them make exosome as a potential way to diagnose and treat diseases. It shows a promising prospect in the development of precision medicine. In this thematic issues, we collected latest research and review papers in this field and hope it will be helpful to the readers who are interested in exosomes as drug delivery vehicles.

The integration of nanotechnology with biology is poised to address current biomedical and human health problems [1, 2]. Recent developments at such interfacial research have shaped novel concepts and products in the area of nanodevices and nanomedicines. It is well established that the advances in the areas of bio-mimetic/bio-inspired nanotechnology, bio-imaging, disease diagnosis, and treatment, would progress with either improvement in existing methods using integration of nanoparticles or development of novel methods for the preparation of nanomaterials [3, 4]. This special issue includes seven articles delving around to provide a comprehensive overview of recent trends and developments of nanotechnology towards multidimensional aspects of biomedical applications. The first contribution covers an overview of nanobiotechnology and cancer nanotechnology submitted by Chaturvedi et al. [5]. This manuscript summarizes the use of nanomaterials for early cancer detection by sensing the targeted biomolecules such as proteins, antibody fragments, and nucleotide (DNA/RNA) fragments serve as cancer biomarkers. Nanoparticles as drug delivery vehicles for the treatment of cancer has been at the frontier of the cancer nanotechnology, which has found to develop novel strategies and smart ways to deal with cancer cells. Several of these examples are covered in this article as well as in the second contribution written by Patel et al. [6]. Topical application of drug-delivering nanoparticles has shown promise towards the treatment of several autoimmune disorders such as Rheumatoid Arthritis, which deals with symptoms such as chronic progressive inflammation and destruction of cartilage and bones. A concise report about the different types of nanomaterials exhibited positive results for Rheumatoid Arthritis treatment has also been presented. Safe delivery of anesthetic agents to the patients remains one of the challenging tasks; therefore, utilizing the capabilities of nanotechnology has been recently realized for the site specific delivery of such drugs. Therefore, we have also included a comprehensive report by Liu et al. describing the synthesis of various nanoformulations of anesthetic drugs and their applications. Today’s medical diagnostics research aims towards molecular imaging to facilitate early diagnosis, identification of disease type, stage of disease and provide fundamental information about pathological processes. The paradigm shift exploits nanomaterial-based probes over traditional single molecule-based contrast agents. Although quantum dots, fluorophore-doped nanomaterials, and other metal-oxides hold excellent promise, development of nanomaterials as artificial enzymes (nanozymes), animal imaging probes such as molecular imaging with X-ray based computerized tomography, ultrasound, and magnetic resonance imaging will be of great use for human health [7-9]. Further, considering the broad spectrum applications of iron oxide nanoparticles, two articles prepared by Shakil et al. [10] and Karakoti and co-workers [11] systematically summarize the current progress and future promises of these magnetic nanoparticles. Protozoan parasites mediated morbidity and mortality has been a serious threat to humans and animals. Among them, Leishmaniasis is a dreaded disease caused by a protozoan parasites Leishmania donovani. Owing to the absence of vaccines for the treatment of leishmaniasis, chemotherapy remains the mainstay for anti-leishmanial therapeutics, which face several limitations and thus results in poor therapeutic efficacy. Several of anti-leishmanial drugs are conjugated with nanoparticles to offer better therapeutic results than naked drugs. In this context, Shah et al have contributed an article summarizing available targeted delivery of pharmacological agents which are expected to enhance the bioavailability, reduce toxicity and circumvent the issues of chemoresistance [12]. Recent developments in the pharmaceutical sector have led to the discharge of drugs in wastewater which could pose threat to the aquatic species and humans. Although recent awareness about the presence of such contaminants in drinking water has raised substantial concerns, very little is known about the fate and ecological impacts of these pollutants. As a result, these pollutants are inevitably introduced to our food chain at trace concentrations and eventually induce toxicity. Focusing on this issue, Agnihotri and co-workers [13] have contributed an article which covers the essential insights about applications of various nanomaterials for the removal of pharmaceutical contaminants from wastewater and soil samples. Undoubtedly, nanotechnology would have a tremendous future due to the unflinching growth and potential to be used as an alternative to solve several of the current generation problems. Incorporation of nanomaterials has led to the construction of new sensors as well as an increase in the sensitivity and performance of existing biosensors. Signal transduction based technologies using nanomaterials has allowed the invention of several novel biosensors. Additionally, the nanoscale dimension further assists the development of nanosensors for rapid and simple detection in vivo. Due to these capabilities, nanotechnology is being looked as the potential technology to provide portable instruments capable of multiplexed analysis of components in extremely low concentrations. However, the release of nanoparticles from consumer products into the environment has been suspected as one of the biggest limitations of nanotechnology. Therefore, it is imperative to fully understand the properties and activities of nanomaterials before it is used for any biomedical applications. In this context, Gupta et al. [14] have summarized potential toxicities aroused by nanoparticles and their possible remedies by considering carbon-based nanomaterials as a model nanoparticle system. The strategies described in this article is not only limited to carbon-based materials and could also be extended to other nanomaterials of biomedical interests. All the valuable contributions presented in this special issue depict the present status and future perspectives in the area by leading experts of the field. This comprehensive issue will be a valuable asset for researchers from all fields which encompasses the expertise from materials science, medicines, engineering, and radiologists together to make nanobiotechnology most rewarding.

With the development of high-throughput sequencing techniques, more and more sequencing data is available, including genomics reads, transcriptomes data, and proteomics sequences, which provide us an opportunity for disease treatment and prevention that takes into account individual variability in environment, lifestyle and genes for each person. Thus, it is critical to develop protein drugs and identify protein drug targets. Application of machine learning techniques in protein drugs and drugs targets discovery is more and more popular because these techniques can extract the essential characteristics of research object and improve accuracies of models, which is needed by all biological scholars [1, 2]. This special issue was hosted in various aspects of the development and application of machine learning techniques in protein drugs and drug targets data analysis. In this special issue, ten works were published for describing the development of drug design and drug target discovery by using machine learning methods. Drug discovery is very important for pharmaceutical industries. At its current stage, it is still an expensive and timeconsuming process for discovering new drugs. Machine learning techniques have been widely applied in the field. Stephenson et al. reviewed the potential application of Artificial Intelligent (AI) techniques in the field of drug discovery [3]. This review provides a survey to understand the current status of machine learning techniques in the drug discovery field within both academic and industrial settings. They also discussed the AI potential future applications and several interesting patterns in drug discovery fields. Peptide-Fc fusion drugs are a category of biological therapeutics in which the Fc region of antibody is fused genetically to a peptide of interest. Ning et al. summarized the key steps of peptide-Fc fusion technology and stressed the main computational resources, tools, and methods that were helpful for the rational design of peptide-Fc fusion drugs [4]. Moreover, they raised open questions about the computeraided molecular design of peptide-Fc fusions. Heat Shock Proteins (HSPs) are molecular chaperones. They are associate with multiple kinds of diseases. Chen et al. summarized the development of HSP families’ classification and prediction by using machine learning methods [5]. Several published online servers were listed which will provide convenience to most of wet-experimental scholars. Protein–peptide recognition and interaction plays an essential role in the orchestration and regulation of cell signaling networks. Li et al. presented a systematic review of applying machine learning techniques to perform the quantitative modeling and prediction of protein– peptide binding affinity, particularly focusing on its implications for therapeutic peptide design [6]. They briefly introduce the physical quantities used to characterize protein–peptide affinity and extend the content of generalized machine learning methods. They also discussed the existing issues and future perspective on the computational prediction of protein–peptide binding affinity. To understand the functions of target proteins binding and regulating by drugs is crucial to against the diseases. Two reviews focused on the drug-target identification. Hu et al. provided a systematic overview of recent work on identifying drug targets [7]. They summarized the published drug-target database, wet- and dry-experimental techniques on drug targets discovery and published results obtained from machine learning method. Zhang et al. focused on the recent advances of drug-target interaction prediction by using machine learning methods [8]. They also listed the published datasets, and introduced features for drugs and targets. Since similarity index are important for prediction, they introduced how to calculate similarities based on training data or published features. Finally, they summarized and compared the performance of different machine learning-based prediction methods. Virus-host protein interactions play essential roles in viral infection and antiviral defenses. Targeting critical viral-host Protein-protein Interactions (PPIs) has enormous application prospects for therapeutics. Using computational method to identify virus-host PPIs could provide new opportunities for gaining biological insights, including applications in disease control. Zheng et al. provided an overview of recent computational approaches for studying virus-host PPI interactions [9]. The pivotal and representative features extracted from relevant sources of biological data were described. They also introduced some state-of-the-art machine learning algorithms in the field and discussed their abilities, weakness and future directions. Cervical cancer is the second most common cancer in women worldwide, which was caused by Human Papillomavirus (HPV). Thus, Yao et al. focused on HPV identification. They discussed the advantage and disadvantage of several classical approaches which have been applied for the risk type prediction of HPV [10]. Especially, many computational methods were proposed for this prediction issue. Cell-penetrating Peptides (CPPs) are important short peptides that can transport drug molecules through the plasma membrane and send these molecules to different cellular organelles. Thus, Wei et al. summarized the machine learning-based CPP identification methods and compared the construction strategies of 11 different computational methods [11]. Furthermore, they pointed out the limitations and difficulties in predicting CPPs. The future development direction of CPP recognition with computational methods was finally discussed. Drug metabolism is one of the most complicated pharmacokinetic properties to be understood and predicted. Xiong et al. reviewed the computational study on cytochrome P450 enzymes which play a key role in the phase I metabolism of foreign compounds including most of drugs [12].

Humans and mammals must successfully evolve metabolic system, to effectively deal with the inevitable exposure to a lot of nutrients and chemicals (xenobiotics) from the exogenous food and environment, especially endogenous toxic metabolic by-products, in order to maintain homeostasis and survive in nature. This exogenous nutrients and chemical defense task are undertaken by the hepatic metabolism and detoxification system mediated by the xenobiotic receptors, which at least include the Pregnane X Receptor (PXR), Constitutive Androstane Receptor (CAR) and aryl hydrocarbon receptor (AhR) [1]. PXR and CAR are the bona fide nuclear receptors, which have been cloned in all vertebrates, indicating the evolutionary conservation for metabolic detoxification [2]. AhR has been identified as ligand activated transcription factor of the bHLH/PAS family, and mediating the toxic responses of dioxins, polycyclic aromatic hydrocarbons and other related compounds [3-4]. It is reported that PXR plays a critical role in organism's metabolic detoxification system by sensing the presence of xenobiotics and triggering detoxification responses. Additionally, PXR has pleiotropic functions in regulating immune and inflammatory responses, cell proliferation, bile acid and cholesterol metabolism, glucose and lipid metabolism, steroid and endocrine homeostasis, as well as bone metabolism. Pu et al. summarized the effects of xenobiotic nuclear receptors on metabolic syndromes. Chen et al. concluded how xenobiotic receptors mediate hepatic glycolipid metabolism. Recent research suggests that the PXR is required for maintaining healthy commensalism between microbiota and gut [5]. Interestingly, the metabolites such as indole derivatives from commensal microbes serve as the ligands for the PXR in intestinal epithelium forming an intricate mutualistic interaction between host and microbiota. AhR recognizes xenobiotics as well as natural compounds such as tryptophan metabolites, dietary components and microbiota-derived factors [6], and it is important for maintenance of homeostasis at mucosal surfaces. AhR activation induces cytochrome P450 1 (CYP1) enzymes, which oxygenate AhR ligands, leading to their metabolic clearance and detoxification [7]. Thus, CYP1 enzymes have an important feedback role that curtails the duration of AhR signaling [6]. It is reported that intestinal epithelial cells serve as gatekeepers for the supply of AhR ligands to the host and emphasize the importance of feedback control in modulating AhR pathway activation [8]. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via IL-22 [9]. Tryptophan mediates the IDO1-AhR axis in host-microbial symbiosis [10]. Ji et al. reviewed the cross-regulatory circuit between AhR and microbiota. Tryptophan metabolite activation of the aryl hydrocarbon receptor regulates IL-10 receptor expression on intestinal epithelia [11]. In addition, other factors have reported to be involved in the crosstalk between nutrients and xenobiotic receptors. Feng et al. concluded Kisspeptin and its effect on mammalian spermatogensis. Zhang et al. summarized the role of E-cadherin in Helicobacter pylori-related gastric diseases. Wang et al. summarized the amino acid metabolism in dairy cows and their regulation in milk synthesis. Zhou et al reviewed soy isoflavones and their effects on xenobiotic metabolism. Abdallah et al. concluded application of traditional Chinese herbal medicine byproducts as dietary feed supplements and antibiotic replacements in animal production. This special issue collects and provides an overview of the current understanding of the pattern of the crosstalk between nutrients and xenobiotic receptors, as well as its dysfunction induced metabolic diseases, particularly the critical signal pathways, which will shed light on revealing potential targets for therapeutics.

A variety of factors can affect the patients' responses to therapeutic drugs, such as race, gender, age, etc., while genetic polymorphisms are the main causes of individual differences in drug responses. The genetic polymorphisms are not only closely related to the incidence of diseases such as tumors, Alzheimers, and Parkisnsons, but also affect the metabolism, activity, and toxicity of the drugs. The studies of genetic polymorphisms on drug metabolizing enzymes, transporters, and targets are helpful to clarify the relationships between gene mutation and efficacy or safety of drugs. Patients could be given different therapies according to different genotypes, which may significantly improve the therapeutic effect. Genetic polymorphisms provide a new way for individualized treatments besides therapeutic drug monitoring. At present, the relationships between genetic polymorphisms of many drugs and clinical outcomes have been very clear. For example, the guideline emphasizes that genetic testing has the vital significance when taking warfarin. However, although genetic polymorphisms of many drugs have been reported, some studies are controversial, it is also necessary to integrate various genetic factors for further research. Therefore, this special issue of Current Drug Metabolism is to publish some valuable reviews on how genetic polymorphisms affect the pharmacokinetics and pharmacodynamic parameters of several therapeutic drugs, including antitumor drugs, antiasthmatic drugs, immunosuppressive agents, anti-infective drug, EGFR Tyrosine Kinase Inhibitors (EGFR-TKIs), and Recombinant Human Growth Hormone (rhGH), new oral anticoagulant, humanized anti-α4 integrin monoclonal antibody, Platelet-Derived Growth Factor Receptor (PDGFR) kinase inhibitors. We aim to provide current genetic research progress on these therapeutic drugs which are widely used in clinic therapy.

Gamma-hydroxybutyrate (GHB) is a potent central nervous system depressant, used as a recreational drug of abuse. It is quite frequently found in forensic investigations of subjects alive or dead. GHB in the form of sodium salt is a registered therapeutic agent approved of by some countries in treating narcolepsy-associated cataplexy and is an adjuvant medication for detoxification and withdrawal in alcohol abusers. GHB is endogenously produced and traces can be found (0.5-1.0 mg/L) in various tissues, including the brain, where it functions as both a precursor and a metabolite of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). Information available indicates that GHB serves as a neurotransmitter or neuromodulator in the GABAergic system, and in particular via binding to the GABA-B receptor subtype. Taking into account the dual nature of this compound, endogenous and exogenous, various points need to be clarified and this special issue aims to focus on them, trying to provide the most updated scientific evidence in this field. Moreover, the role of new GHB metabolites, such as GHB-glucuronide (GHB-Gluc) and the sulfonated metabolite of GHB (GHB-SUL) and their detection window in biological samples, with particular emphasis on alternative matrices, will be given for forensic purposes, especially in cases of drug facilitated sexual assault (DFSA), and clinical purposes both in the short and long-term monitoring of patients under sodium oxybate treatment.

Tumor is one of the most serious threats to human beings. Benefiting from the fast development of nanotechnology, many kinds of nanoparticles that constructed from various nanomaterials were developed for tumor diagnosis and therapy. Nanoparticles have gained great attention of both academy and industry. However, few nanoparticles were approved for clinical application although thousands were developed in lab. Therefore, in this theme issue, we invited several contributors to discuss the application of various kinds of nanoparticles in tumor targeting drug delivery, as well as their advantages and shortages. Based on their good biocompatibility and low toxicity, polymeric nanoparticles have gained much attention in gene and drug delivery to tumor. However, the drug delivery efficiency by polymeric nanoparticles is greatly hindered by the rapid opsonization, phagocytic uptake and subsequent clearance from bloodstream. Therefore, in the first review, Hu et al. firstly discussed the factors that influence the blood circulation of polymeric nanoparticles, including particle size, shape, zeta potential and hydrophilicity. Then some natural and synthetic polymers used in the constructing of nanoparticles were reviewed, such as gelatin, polysaccharides, cyclodextrin, and synthetic polymers. While several preparation methods were also discussed, including polymerization techniques, precipitation techniques, film extension techniques, and particle replication in non-wetting templates. Finally, methods to achieve long blood circulation time were reviewed. In the review provided by Zhang et al., authors further discussed the strategies in long circulating drug delivery by nanoparticles. To achieve the long blood circulation time, PEGylation is widely used in modification surface of nanoparticles to inhibit the adsorption of opsonins in blood. As an alternative of finding new nanomaterials especially new surface coating materials, biomimetic nanoparticles showed great potential because they can adopt the intrinsic long circulation behavior of biological components, such as red blood cells, cancer cells, macrophages, bacteria, viruses and lipoproteins. The application of these strategies and the constructed nanoparticles were detailed reviewed in the paper. Safety of nanomaterials is a great concern for clinical application, that is why only few formulations were approved by Food and Drug Administration (FDA) of US. To meet the safety concern, natural polymers are good candidates to constructing nanoparticles. Polysaccharide is one of the most widely explored and used natural polymers, and many kinds of derives were developed to provide excellent properties in drug delivery. In the review, Dr. Tong and Dr. Ma summarized the representative examples of polysaccharides used in drug delivery, such as chitosan, hyaluronic acid, dextran and pullulan. Because of their widely application in tumor targeting diagnosis and treatment, the reviewed discussed several aspects of the application of polysaccharide, including gene delivery, small molecular drug delivery, no matter polysaccharide- drug conjugates or drug encapsulation, combinational drug delivery, and finally theranostics. In the review, many examples were provided with in-deep discussion. As a supplement to the natural polymers, nature products could be directly used in treatment of cancers. Therefore, Dr. Cai and Dr. Yu reviewed the application of natural products in cancer therapy by targeting the apoptosis pathways. In the review, key proteins involved in the regulation of apoptosis were firstly summarized, including Cytochrome c, Bcl-2 family, p53, Fas, Survivin, Caspase family, Nuclear factor- B, and Protein Kinase B. Then various kinds of natural products that can target these proteins were reviewed. Gold nanoparticles are most widely used inorganic nanomaterials in cancer diagnosis and therapy, while many kinds of anisotropic gold nanoparticles are developed, including gold nanospheres, gold nanoclusters, one-dimensional gold nanorods, two-dimensional gold nanoplates, gold nanoshells, platonic gold nanoparticles, hollow gold nanoparticles and other types of gold nanoparticles. In the review provided by Dr. Shevtsov et al., the various synthesis methods for these kinds of gold nanoparticles were summarized. Then the application of gold nanoparticles in drug delivery was reviewed. Gold nanoparticles have been used in many aspects of tumor treatment and diagnosis, such as modification tumor microenvironment, radiosensitization, photothermal therapy, and photodynamic therapy. All these researches demonstrated the great potential of gold nanoparticles in tumor management. At last, as a kind of cancers with highest incidence, lung cancer was paid with particular attention. Zheng et al. reviewed the nanoparticles in management of lung cancer, including polymeric nanoparticles, lipid nanoparticles, human serum albumin nanoparticles, and inorganic nanoparticles. Then the various models used for different application routes were reviewed. Finally, the clinical application of these administration routes and formulations were discussed.

Mental disorders such schizophrenia, depression, bipolar and anxiety disorders are leading causes of disability and multimorbidity in the modern society. In recent years, major advances were made in order to understand the molecular basis of these disorders aiming to discover potential new drugs. Unfortunately, the majority of these efforts have been unsuccessful. Many other studies have been focused on understanding the mechanism of action of drugs used for the treatment of neuropsychiatric disorders, such as antidepressants, mood stabilizers and antipsychotics using isolated systems. Many incredible discoveries were made which allowed us to develop better treatment options to improve the quality of life of patients struggling with these disorders. Today, clinicians and scientists are combining forces to better understand different connections of the brain-body relationship that were refuted for many years because of the general idea of the brain as an independent and isolated tissue. The concept of a two-way relationship between depression and cardiovascular disease, or the gut-brain axis is only gaining more space and credibility. We are in the moment of understanding how our complex body is interconnected in the way that a single insult in a remote part of our body could lead to molecular changes in our brain. We are also better understanding the side effects of distinct drugs, such as antidepressants, and their impact on a population with cardiovascular disease or the relationship between long-term lithium intake and cancer proliferation. More studies are still needed to confirm these suggestions; however, they are thought-provoking. This thematic issue, devoted to the study of current pharmacological treatments involved in mental disorders introduce an interesting interface intended to explore (i) the safety limits of the use of antidepressants on cardiovascular function [1], (ii) the cross-talk between inflammation in depression and cardiovascular disease [2], (iii) the involvement of microbiota in the etiopathogenesis of mental illness [3], (iv) the relationship between lithium intake and cancer proliferation [4] and (v) the applicability of targeting GSK-3B for several incurable neuropsychiatric disorders [5]. It is evident that science reached a time where scientists and clinicians are combining strengths to better comprehend the molecular basis of pharmacological treatments to study the diseases as they occur; in combination, and not isolated. In this new era of technology and information, combining forces in a multidisciplinary environment to understand the pathological basis will only improve the treatment options and the quality of life of patients with psychiatric disorders.

Chronic kidney disease (CKD) leading to kidney failure is becoming a global public health problem. Acute kidney injury (AKI) is also a major kidney disease characterized by a rapid decline of renal function. Drug-induced nephrotoxicity is a contributing factor to AKI in 19-25% of critically ill patients. Drugs exert their toxic effects to cause nephrotoxicity by one or more common pathogenic mechanisms. The progressive loss of kidney function associated with CKD not only leads to impaired renal excretion of numerous drugs and their metabolites in the kidneys, but also alters the non-renal disposition of moieties that are extensively metabolized by the liver. Various alterations in activity of metabolic enzyme system have been reported in CKD models, for example, reductions in expression and activity of hepatic cytochrome P450 (CYP) enzymes including CYP3A1, CYP3A2, CYP2C11, and other enzymes such as N-acetyltransferases. What’s more, other mechanisms such as the dysregulation of drug transporter systems are involved in decreasing the clearance of drugs in renal failure. With the development of renal failure, the renal secretion of organic ions mediated by organic anion transporters (OATs) and organic cation transporters (OCTs) is decreased. Some organic anionic uremic toxins may directly inhibit the renal excretion of various drugs and endogenous organic acids by competitively inhibiting OATs. The objective of this mini-thematic issue is to report recent studies about most common mechanisms of drug-induced nephrotoxicity and prevention strategies, the alterations of drug enzymes and transporters in the kidney and liver in renal failure, the potential model systems to predict drug efficacy, interactions, and drug-induced kidney injury in drug development.

Neurological disorders cover a wide range of diseases; suffering patients all around the world. A study in UK shows about six percent of the population involved with neurological disorders [1]. Also, investigations stated that the imposed cost of these disorders is an important challenge for European societies [2]. Therefore, there are too many investigations to find new medical approaches and remedies to treat or manage neurological disorders. Natural products as well as complementary and alternative therapies are as the sources to find such therapeutics that are going to be more popular in the society. There are too many traditional and complementary systems of medicine, mostly with historical roots in ancient eras like Chinese medicine, Persian medicine, Ayurveda, Homeopathy, etc. [3] Alongside raising the popularity of using natural and traditional medications, interest of researchers to evaluate their efficacy and safety is going to be raise up. On the other hand, this popularity causes some concerns including the safety and probable interactions between these remedies with common drugs. Therefore, investigations to find the efficacy and safety of them with the help of accepted and academic methods are too important. World Health Organization (WHO) approves and encourages traditional therapies integrated with current and conventional medicine. It means using the opportunities in both medical systems, traditional and conventional medicines [4]. It is important to integrate Traditional and Complementary Medicine (T&CM) approaches to current medical systems. It is not only necessary for using T&CM opportunities to manage and treat neurological disorders and decrease the costs of treatment, but to find any probable side effects and interactions with such remedies. Therefore, in the first step, it needs scientific investigations to find T&CM drugs’ efficacy, safety and toxicology and then, in the next step training the neurologists and pharmacists is too important. Therefore, this thematic issue of Current Drug Metabolism aims to publish some valuable reviews on the principles, suggestions, efficacy of drugs and also herb-drug interactions of some types of T&CM systems in some neurological disorders; providing scientific data and discussions for medical practitioners, pharmacists and researchers in this field.

This thematic issue will provide a platform to share comprehensive information on advances and recent trends in various prophylactic and therapeutic regimens to effectively combat various diseases and other health problems, both infectious and non-infectious posing challenge to the humans and their companion animals (livestock & poultry). It will focus mainly on the novel, emerging and valuable alternate / complementary frontier therapeutic options especially in the era of emerging and rising drug resistance in microbial pathogens and increasing health disorders and conditions of high concerns due to changing life style and other various predisposing factors. Advances and interdisciplinary approaches of biotechnology, molecular biology, genetics, cellular immunology, immunomics, proteomics, pharmacology, bioinformatics, nanotechnology and others for designing and developing newer and effective therapeutic modules would be given priority. These will include phages, enzybiotics, apoptins, cytokines, monoclonal antibodies, egg yolk antibodies, TLR, stem cells, si-RNA, nanomedicines, nutritional immunomodulation, probiotics, antioxidants, phytonutrients, and herbal medicines, which could play promising role in curbing evolving pathogenic threats by their potent antimicrobial potential, treating non-infectious diseases, metabolic disorders, cancers as well as various general health problems. Other potential candidates being explored for targeting development of valuable medicines, drugs, pharmaceuticals, immunotherapeutics, antitoxins, tissue growth factors, gene therapy, regenerative medicines, therapeutic biologics, modern vaccines and vaccines based therapies will also be considered. Trends and advances in pharmacogenomics aided drug development and therapeutics, pharmacokinetics, pharmacodynamics and metabolism of effective/newer drugs and medicines, upcoming drug designing and novel drug delivery methods will also be given due attention. The compilation will be useful for medical and veterinary professionals, clinicians, researchers, students/scholars, public health experts, animal producers, and pharmaceutical industry in designing and adapting effective and safer therapeutics from clinics to the laboratory for countering important diseases. This thematic issue will accept submissions of comprehensive review papers on above mentioned topics / theme with their basics, modes of action, medicinal values, beneficial health applications, modern trends and advances, perspectives, which could lead to designing and development of effective therapeutics, drugs/medicines, nutraceuticals and pharmaceuticals in the area of biomedicine with an aim to safeguard health of both humans and animals in a better way.

Recent developments in nanomaterials for the therapy of deadliest diseases have gained significant interest because of their advantages, such as reduction in systemic toxicity, easy surface functionalization with passivation and targeting moieties, and enhanced drug accumulation in specific tissue. Nanomedicines and nanomaterials can be administrated by different strategies, including oral, local, intravenous, and transarterial administration, which are the underlying determinants for their therapeutic efficacy, pharmacokinetics and pharmacodynamics. In order to optimize the therapeutic outcomes, careful design and synthesis of nanomedicines are guided by the administration strategies. It requires a broad-system view for innovative nanomaterials and their clinical applications. The aim and scope of the issue is to introduce Current Drug Metabolism readers to this important topic of efficacy, toxicology, and PK/PD of nanomedicine administrated by different strategies. I would like to thank Editor-in-Chief, Michael Sinz, for his support and all authors for their contribution to this special issue. I am grateful for all peer reviewers’ time and expertise, which help to improve quality of articles. I also thank Maryam Shaikh for the excellent coordination in publication process.

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